Research in the Cell Biology Section, Neurogenetics Branch focuses on the molecular mechanisms underlying a number of neurodegenerative disorders, including mitochondrial disorders, Parkinson disease, peripheral neuropathies, and the hereditary spastic paraplegias (HSPs). These disorders, which together afflict millions of Americans, worsen insidiously over a number of years, and treatment options are limited for the vast majority of them. Our laboratory is investigating inherited forms of these disorders, using molecular and cell biology approaches to study how mutations in disease genes ultimately result in cellular dysfunction. In this project, we are emphasizing investigations into the regulation of mitochondrial morphology within cells. Indeed, fusion and fission events that regulate mitochondrial morphology are essential for proper mitochondrial function, and their regulation is increasingly recognized in diverse cellular functions. Mitochondrial fission events in mammals are orchestrated by at least two proteins; the dynamin-related protein Drp1 and the integral membrane protein Fis1. The reciprocal process of mitochondrial fusion also requires large GTPases of the dynamin superfamily: OPA1 and the mitofusins Mfn1 and Mfn2. Since mutations in Drp1, Mfn2, and OPA1 have been identified in patients with inherited neurological disorders, and there is prominent fragmentation of mitochondria during programmed cell death, insights into the regulation of these processes is highly relevant clinically. In the past, we published a study of the Drp1 A395D mutation that caused a neonatally fatal mitochondrial disorder due to markedly diminished mitochondrial fission. In this project, we were able to show that this mutation resulted in loss of higher-order multimeric interactions of the Drp1 protein. In complementary studies, we have now identified mutations in Drp1 that dramatically stabilizes higher-order Drp1 structures. Lastly, in ongoing studies we have identified a number of Drp1-interacting proteins that may be involved in the proper distribution of mitochondria within cells as well as novel proteins that regulate the mitochondrial fission/fusion balance through unknown mechanisms. We continue to evaluate patients with these types of disorders, and these studies will spur additional mechanistic investigations. More recently, we have been focusing our efforts on mitochondrial dynamics and function in certain forms of hereditary spastic paraplegia, most notably SPG11, SPG15 qand SPG48. In 2018, we published a study in Human Molecular Genetics in collaboration with Dr. Xue-Jun Li, showing that induced pluripotent stem cell (iPSC)-derived neurons have impairments in mitochondrial structure and function within axons that can be suppressed by inhibition of mitochondrial fission. Also, we have initiated a new project with Dr. Richard Wade-Martins investigating mitochondrial function in iPSCs from patients with genetic forms of Parkinson disease. Together, these studies are continuing to provide critical insights into the regulation of mitochondrial morphology within neurons, an area of clear clinical relevance and importance.